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Clinical Genetics > Functional Genomics: Balance, Order and Control > Flashcards

Functional Genomics: Balance, Order and Control Flashcards

1
Q

What factors are linked to control of the genome?

A
  • 3.2 billion bases of dsDNA from mother (22 autosomes plus X)
  • 3.2 billion bases of dsDNA from father (22 autosomes plus either X or Y)
  • mtDNA from mother
  • Transcriptional control
  • Gene product function
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2
Q

What is functional genomics?

A 
Growth
Differentiation
Function
Stability
Death
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3
Q

When is the genome visible?

A

Metaphase- chromosomes condense

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4
Q

What is the karyotype?

A

Shows pairs of chromosomes

  • Biggest chromosome= pair 1
  • Smallest= pair 22
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5
Q

What are the features of the chromosome?

A

-Centromere
-Telomere
-Width (1.9nm) and axial length
=Each turn= 10 base pairs

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6
Q

How is DNA packed?

A

-Nucleosome= DNA wrapped around optima of proteins/ histones

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7
Q

What is the packing ratio?

A

Length of native DNA strand/ length after condensation

-Nucleosomes have packing ratio = 6

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8
Q

How is the chromosome compacted?

A

-Condensin 1= lateral compaction of chromosomes (metaphase)
-Condensin 2= axial shortening of chromosomes (prophase)
*Ring structures
Proteins are separate from each other
Mutations in components of multimer Condensin= brain does not grow enough, bridges between metaphase bundles so no segregation

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9
Q

Describe the cohesin cycle

A

-Centromere= kinetochores attached
-Attachment due to ring like structures made up of SMC1A and SMC3= cohesion unit
-Encompasses dsDNA, regulated by acetylation
-Allows metaphase chromosomes to separate
= cohesion molecules lock chromosomes together at kinetochores
= kinetochores that assembles at centromere exert pulling force
= specific strength= signal triggers release of cohesion ring simultaneously

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10
Q

What are the disorders of cohesion function?

A 
-Roberts syndrome
=Prenatal growth failure
=Limb malformations
=Cleft lip and palate
=Facial dysmorphism

=Biallelic (loss of function) mutations in ESCO2 (acetylates)
=Premature centromere separation - centromeric puffing as stuck
=Lagging chromosomes in anaphase

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11
Q

What are telomeres?

A
  • Stop ends of chromosomes from sticking together
  • Long single strands of DNA using internal RNA template so repeat at end of chromosome
  • Shorten through cell division= biological clock
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12
Q

What is dyskeratosis congenita and how does it present?

A 
-Disorder of telomere formation
=dysplastic nails
=reticular pigmentation
=oral leukoplakia
=bone marrow failure 
=myelodysplastic syndrome 
=acute myelogenous leukemia
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13
Q

Describe the genetics of dyskeratosis congenita

A

-short telomeres
-locus heterogeneity
=X linked
(DKC1)
-Autosomal dominant
(TERC, TERT, TINF2)
-Autosomal recessive
(NOP10, NHP2, WRAP53, PARN)

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14
Q

What is euploidy?

A

-Normal constitution of chromosomes= 46, with two X/ one X and one Y

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15
Q

What is polyploidy?

A

Extra copies of whole genome

-Usually in plants

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16
Q

What is trisomy?

A

Extra copy of one chromosome
=autosomal
=X chromosome

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17
Q

What is monosomy

A

Lost a pair of chromosomes
=Turner syndrome (X chromosome)
=Difficult to determine in live infants

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18
Q

What is the commonest type of polyploidy we see in humans?

A

Triploidy
- An extra copy of maternal genome in female embryo
=Occurs in 1% of early pregnancy losses
=Not seen in babies or children
=Extra paternal copy of genome -> hydatidiform mole (like cancer of placenta)
=Liveborn infants usually diploid/ triploid mosaic (69 XXX karyotype)

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19
Q

What are the common trisomy’s (autosomal)?

A
  • 21= Down syndrome
  • 18= Edward syndrome (lethal in early life, small and multiple malformations)
  • 13= Patau syndrome (bilateral cleft of lip etc)
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20
Q

What are disorders of the sex chromosomes?

A 
-Klinefelter syndrome
=47 XXY
=Extra copy of X
=1 in 500 boys
=Testes dont develop endocrine function properly, morphological difference at puberty, cannot produce enough testosterone= gynecomastia
=Usually infertile
*Replace testosterone
-Turner syndrome
=45 X monosomy
=Ovaries develop initially then regress so endocrine function lost 
=Can't produce enough oestrogen
=90% lost in early pregnancy due to foetal oedema
-47 XYY= impulse control problems
=47 XXX= mild cognitive impairment
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21
Q

Why is balance so important?

A

-10% genes encode for proteins that control the expression of other genes
=transcription factors
-Triploid= 1.5 fold dosage change for whole genome, 3 copies of transcription of factor gene= 3 copies of target gene
-Trisomy= 1.5 fold change for 2.4% of the genome= 3 copies of chr18 TFs and 2 copies of most TFs= 2 copies of target gene

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22
Q

Describe male meiosis

A

-Single progenitor cell
-2 meiotic divisions
-4 cells= gametes
*haploid
Takes 74 hours per division, starts at puberty (12)

23
Q

Describe female meiosis

A

2 meiotic divisions but only one egg made- other daughter cells redundant (1:1)

  • M1 begins in foetal life
  • Meiosis ends only after fertilisation
24
Q

How does meiosis work?

A
  • Homologous chromosomes come together to form complex= homologous pairing (maternal and paternal)- enzymes scan to find identical DNA to allow pairing
  • Homologous recombination= swapping of material so mix the maternal and paternal chromosomes; efficient way to distribute advantageous traits
25
Q

What is M1 non-disjunction?

A
  • Instead of homologous pairs splitting= pulled into one daughter
  • Gametes with 22 pairs= not viable so will not see gametes
  • 24 chromosome cells, fertilised= three copies of a chromosome
  • Trisomy
26
Q

What is M2 non-disjunction?

A

-Sister chromatids pulled into one gamete, second gamete has no chromatids so lost

27
Q

How can mitosis lead to trisomy?

A
  • Embryo/ zygote
  • First division
  • Non-disjunction= either two copies of paternal or maternal sister chromatids pulled into one cell (monosomy in other so lost)
  • Mosaicism after first division, at first division= non-mosaic
28
Q

How common is each of the ways to get trisomy 21?

A
  • M1 non-disjunction= 69% maternal, 23% paternal
  • M2 non-disjunction= 22% M, 36% P
  • Mitotic non-disjunction= 2% M, 19% P
    (91. 5%M, 8.5% P overall)
29
Q

How is developmental gene expression controlled in interphase cells?

A

Loops

  • Loop initiation
  • Loop extrusion
  • Insulated developmental locus from mature loop via cohesion ring
30
Q

What malformations are caused by mutation to PAX6?

A
  • Loss of function to transcription factor, monoallelic
  • Chromosome 11
  • WAGR syndrome= Wilms tumour (kidney), Aniridia (iris doesn’t form), Genitourinary anomalies, Mental Retardation
31
Q

How do deletions occur?

A

-Non-homologous end joining= homologous pairing, recombination, depends where breaks occur
-Within chromosome
=Interstitial deletion= double stranded breaks occur within one arm of the chromosome
=Terminal deletion= lose a fragment of chromosome, repaired with telomerase
-Outside chromosome= double stranded breaks with non-homologous repair so different chromosomes (reciprocal balanced translocation)

32
Q

Examples of NHEJ Contiguous Gene Syndromes

A
  • recognised via phenotype as a result of haploinsufficiency for one or more high-penetrant genes
  • Miller-Dieker Syndrome
  • Cri du Chat Syndrome
  • Retinoblastoma
  • Rubinstein-Taybi Syndrome
  • Wolf-Hirschhorn Syndrome
  • WAGR Syndrome
33
Q

Describe Miller-Dieker Syndrome

A

Distinctive facial appearance, lissencephaly, severe learning disability, heart defects, growth retardation and seizures
Major genes LIS1 and 14-3-3

34
Q

Describe Cru du Chat Syndrome

A

Microcephaly, micrognathia, epicanthic folds, and high-pitched cry
Major genes unknown

35
Q

Describe Retinoblastoma

A

Retinoblastoma, learning disability

RB1

36
Q

Describe Rubinstein-Taybi Syndrome

A

Distinctive facial appearance, short stature, broad thumbs

CREB deletions account for <10% cases

37
Q

Describe Wolf-Hirschhorn Syndrome

A

Distinctive facial appearance, seizures, short stature, cleft lip, coloboma
WHSC1

38
Q

Describe WAGR Syndrome

A

Aniridia, Wilms tumour, male genital tract malformations, learning disability
PAX6, WT1

39
Q

What problems in meiosis lead to reciprocal translocations?

A
  • Meiosis requires the homologues to pair
  • Create complex structures called quadrivalents to resolve
  • Reduces efficiency of meiosis, so sperm count lower
40
Q

What problems are caused by segregation of reciprocal translocated chromosomes?

A
  • Problems when normal chromosome segregated with derivative so different amounts of chromosome
  • Imbalance in embryo
  • Interrupt gene= clinical effect
41
Q

What can the breakpoints do?

A
  • Direct gene disruption
  • Change in chromatin state
  • Cis-regulatory gain or loss
42
Q

What is non-allelic homologous recombination?

A
  • pairing of homologous chromosomes during meiosis, mediated by scanning that identify homologous regions of DNA
  • Segments of low copy tandem repeats (long, identical between and within homologues)= loop formation= deletion or duplication
  • Non-allelic= not in right place
43
Q

Examples of microdeletion syndromes

A
  • Di George/ velocardiofacial syndrome
  • Prader Willi Syndrome
  • Angelman Syndrome
  • Williams Syndrome
  • Smith-Magenis Syndrome
44
Q

Describe Di George Syndrome

A

Cardiac outflow tract defects, distinctive facial appearance, thymic hypoplasia, cleft palate and hypocalcaemia. Major gene= TBX1 (cardiac defects and cleft palate)
-1 in 4000

45
Q

Describe Prader Willi Syndrome

A

Distinctive facial appearance, hyperphagia, small hands and feet, distinct behavioural phenotype. Imprinted region, deletions on paternal allele in 70% cases
-1 in 15000

46
Q

Describe Angelman Syndrome

A

Distinctive facial appearance, absent speech, EEG abnormality, characteristic gait,. Imprinted region, deletions on maternal allele in UBE3A
-1 in 15000

47
Q

Describe Williams Syndrome

A

Distinctive facial appearance, supravalvular aortic stenosis, learning disability and infantile hypercalcaemia. Major gene for supravalvular aortic stenosis is Elastin
-1 in 10000

48
Q

Describe Smith-Magenis Syndrome

A

Distinctive facial appearance and behavioural phenotype, self-injury and REM sleep abnormalities. Major gene seems to be RAI1
-1 in 25000

49
Q

What are acrocentric chromosomes?

A
  • Chromosome 13, 14, 15, 21 and 22
  • Centromeres at the end of the chromosomes (not metacentric)
  • Short arms are similar between all acrocentric chromosomes (sequences similar)- factories for components of ribosomes
50
Q

What is Robertsonian translocation?

A
  • 1 in 900
  • short arm of one acrocentric chromosome fused with a different acrocentric chromosome
  • 45 chromosomes not 46 but no loss of unique genetic material
  • Balanced
51
Q

What is the problem with Robertsonian translocation?

A
  • Healthy but some infertility to some degree
  • Problem occurs at meiosis 1
  • Homologous pairing occurs in unusual way, three non-identical chromosomes pair
  • Unbalanced forms with not the right amount of genetic material
  • Non-viable or trisomy
52
Q

Overall, what are the structural chromosomal anomalies?

A
  • Structural change

- Meiotic mechanisms

53
Q

What are the structural changes?

A
  • Deletion
  • Duplication
  • Translocation
54
Q

What are the meiotic mechanisms?

A

-Non-homologous end-joining
=mostly unique
=may be cytogenetically visible or cryptic
-Non-allelic homologous recombination
=recurrent
=common
=basis of most normal copy number variation

Clinical Genetics (9 decks)

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